(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone of formula I is commonly known as “Romidepsin”.
Romidepsin is a natural product and it is belongs to a class of histone deacetylase (HDAC) inhibitor, bicyclic depsipeptide. Romidepsin is approved for the treatment of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior systemic therapy and it is marketed under the brand name of Istodax®.
U.S. Pat. No. 4,977,138 assigned to Fujisawa first disclosed the Romidepsin which is produced by fermantation of Chromobacterium vilolaceum. 
Journal of Organic Chemistry 2008, 73, 9353-9361 reported a process for the preparation of Romidepsin as shown below:

(E)-5-(Tritylthio)pent-2-enal of formula (VIII) and (6R,9S,12S,13R) methyl 13-hydroxy-6-isopropyl-2,2-dimethyl-4,7,10-trioxo-9-(triphenylmethyl thiomethyl)-3-oxa-5,8,11-triazatetradecane-12-carboxylate of formula (XII) are key materials used in the preparation of intermediates of formulae II and III which are further coupling to produce Romidepsin.
The main drawback of the above process is the use of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as a coupling agent. PyBOP coupling agent is very difficult to handle and its contamination remains in the reaction mixture as it is not easily washable. Its removal from the product requires repeated column purifications which is commercially not viable.
Moreover, low temperatures are preferred for the condensation reactions (if the starting materials are chiral) which can control the racemization during the reaction. Using PyBOP and its analogue reagent (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) requires high temperatures for carrying out reaction. Hence the use of condensation agents like BOP and PyBOP are not preferred for the coupling of chiral intermediates which lead to formation of racemic impurities and poor yield of the desired product.
Journal of American Chemical Society 1996, 7237-7238 reported a process for the preparation of Romidepsin comprising reacting the methyl pentadienoate with tritylthiol (also known as tritylthiol) in the presence Cs2CO3 followed by purification from flash chromatography to produce (2E)-5-tritylthio-2-pentenoic acid methyl ester, which is further reducing with diisobutyl aluminium hydride (DIBAL) and purified by flash chromatography to produce (2E)-5-tritylthio-2-pentenol. This (2E)-5-tritylthio-2-pentenol is oxidizing with oxalyl chloride in presence of dimethylsulfoxide (DMSO) followed by purification from flash chromatography to produce (E)-5-(tritylthio)pent-2-enal. This (E)-5-(tritylthio)pent-2-enal is reacted with O-benzyl, O-TMS ketene in presence of Ti(IV) catalyst to produce the aldol product which is hydrolyzed followed by condensation with D-valyl-D-cysteinyl-(S-trityl)-(Z)-dehydrobutinyl-L-valine, methyl ester to yield bis S-trityl ester product. This bis S-trityl ester product is hydrolyzed and reacted with DIAD in presence of PPh3 and TsOH.H2O to produce bis-(S-trityl) lactone which is further reacted with iodine in MeOH to produce Romidepsin.
The major drawback with the above prior art process is the use of BOP as a coupling agent which generates carcinogenic by-product hexamethylphosphoramide (HMPA). Therefore the handling of the BOP and the absence study for its by-product is highly critical. It is not suitable for a large scale process, therefore there is a need to develop an alternate process by avoiding the use of condensing agents like BOP.
Another disadvantage of the above process is the formation of unwanted β,γ isomer i.e. (3E)-5-tritylthio-3-pentenoic acid methyl ester as shown below

Repeated purifications are required to remove this β,γ-isomer impurity which is very time consuming process and results decrease in the purity of final product.
Another disadvantage of the above process is oxidation involves the usage of oxalyl chloride in presence of DMSO and triethylamine in DCM solvent at −78° C. under nitrogen atmosphere. Handling of this reaction at very low temperature is highly critical and the by-product (dimethyl sulfide gas) evolved in this reaction which is unbearable and highly pungent smell.
Organic Biomolecular Chemistry 2011, 9, 3825-3833 reported a process for the preparation of (E)-5-(tritylthio)pent-2-enal of formula (VIII) comprising reaction of acrolein with tritylthiol to produce 3-tritylthiopropanal of formula (IX) which is further reacting with monoethyl malonate to produce the mixture of ethyl (E)-5-(tritylthio)pent-2-enoate of formula (X) and ethyl (E)-5-(tritylthio)pent-3-enoate of formula (Xa) followed by reducing with DIBAL to get the mixture of (E)-5-(tritylthio)pent-2-enol of formula (XI) and (E)-5-(tritylthio)pent-3-enol of formula (XIa) and finally oxidizing with oxalyl chloride in presence of DMSO to produce (E)-5-(tritylthio)pent-2-enal of formula (VIII).
The process is schematically shown as follows:

The major disadvantages with the above prior-art process are the formation of mixture of isomers such as ethyl (E)-5-(tritylthio)pent-3-enoate (X) and ethyl (E)-5-(tritylthio)pent-2-enoate (Xa); and (E)-5-(tritylthio)pent-3-enal (XI) & (E)-5-(tritylthio)pent-2-enal (XIa). Moreover, in this article, these isomers are separated by using column chromatography which is not suitable for industrial scale preparations.
Synlett 2012, 23(5), 783-787 reported a process for the preparation of (E)-5-(tritylthio)pent-2-enal of formula VIII comprising, reaction of acrolein with tritylthiol to give 3-(tritylthio)propanal of formula IX which is condensed with ethyl 2-(triphenylphosphoranylidene) acetate to produce (E)-ethyl 5-(tritylthio)pent-2-enoate of formula X followed by reducing with DIBAL-H and further oxidizing by Dess-Martine periodinane to produce (E)-5-(tritylthio)pent-2-enal of formula VIII.
The process is schematically shown as follows:

The major disadvantage with the above prior-art process is the formation of triphenylphosphine oxide (TPPO) and ethyl (Z)-5-(tritylthio)pent-2-enoate of formula (Xb) as an impurities.

Impurity of formula (Xb) is generated along with required isomer ethyl (E)-5-(tritylthio)pent-2-enoate of formula (X).
This unwanted isomer or impurity of formula Xb is carried over in to the next stages and caused to the increase in impurities. Accordingly, the yield of required (E)-5-(tritylthio)pent-2-enal compound is reduced and also more purification steps are required to remove the impurities.
Removing TPPO impurity is very difficult as it is not soluble in most of organic solvents. TPPO impurity and unwanted isomer of formula Xb are soluble in alcohol solvents.
All the above prior art processes involves the use of column and flash chromatography methods to remove the TPPO and unwanted (Z)-5-(tritylthio)pent-2-enoate isomer of formula (Xb), which is tedious, laborious, requiring repeated purifications and also involving the use of large quantities of solvents. Hence it is not suitable at industrial scale operations.
Hence, there is a need to develop an improved process which is industrially feasible, eco-friendly, cost effective for the preparation of (E)-5-(tritylthio)pent-2-enal of formula X.
The present inventors had developed an improved process for the preparation of Romidepsin by avoiding all the aforementioned drawbacks in the prior art processes.
The present invention is also related to an improved process for the preparation of (E)-5-(tritylthio)pent-2-enal of formula (VIII) and (6R,9S,12S,13R) methyl 13-hydroxy-6-isopropyl-2,2-dimethyl-4,7,10-trioxo-9-(triphenylmethyl thiomethyl)-3-oxa-5,8,11-triazatetradecane-12-carboxylate of formula (XII) which are key components used in the preparation of vital intermediates of formulae (II) and (III) of Romidepsin.